Gestational diabetes mellitus (GDM) negatively impacts maternal cardiovascular function and placental development. GDM causes placental insufficiency, disrupts spiral artery remodeling, and increases the risk of intrauterine growth restriction, preeclampsia, preterm birth, and fetal loss. Pregnancy-Associated Plasma Protein A has been implicated in GDM, however, its paralog Pregnancy-Associated Plasma Protein A2 (PAPPA2) remains understudied. Upstream, TGF-b-SMAD3 signaling controls PAPPA2 expression and secretion. Downstream, PAPPA2 regulates insulin-like growth factor (IGF) signaling, which is essential for trophoblast differentiation, invasion, and spiral artery remodeling. PAPPA2 modulation in mice alters offspring growth. In humans, PAPPA2 expression is elevated in preeclampsia and intrauterine growth restriction; however, the mechanisms by which hyperglycemia affects placental PAPPA2 signaling remain unknown. Using an established GDM rat model we directly test our hypothesis that gestational hyperglycemia disrupts zonal distribution in the rat placenta, alters fetal growth outcomes, and impairs PAPPA2 signaling. Rats were mated in house and treated with a single tail vein injection of Streptozotocin (STZ) or Citrate Buffer (Vehicle) on gestational day (GD) 6.5. There was no difference in pre-injection blood glucose levels between groups (n = 6-8; P > 0.05). On GD 13.5 or 18.5 dams were euthanized and tissues collected for downstream molecular analyses. STZ-treated dams had significantly increased blood glucose at tissue collection (GD 13.5 or GD 18.5) compared to vehicle-treated dams (n=3-5/group; P 0.05). Placental tissue integrity was compromised in STZ-treated dams, with placentas exhibiting malformations at collection. PAPPA2 expression was increased following STZ treatment in whole placentas collected on GD 13.5 (n = 3-6; P = 0.05), but not on GD 18.5 (P = 0.78). Additionally, placental SMAD3, MAPK, mTOR, and ASCL2 expression was not different between groups or gestational time points (P > 0.05). These findings align with clinical observations of elevated PAPPA2 in GDM pregnancies and suggest possible alterations in placental PAPPA2 signaling under hyperglycemia. Further studies are needed to determine its impact on upstream and downstream pathways. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Tucker et al. (Fri,) studied this question.